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The North Atlantic subpolar gyre (SPG) plays a crucial role in determining the regional ocean surface temperature (SST), which has profound implications on the surrounding continental and coastal climate. Here, we analyze the Max Planck Institute-Grand Ensemble global warming experiments and show that the SPG can evolve in two distinct phases under continuous global warming. In the first phase, as the global mean surface temperature approaches 2-K warming, the eastern SPG intensifies in combination with a weakening Atlantic meridional overturning circulation (AMOC), accompanied by a cooling of subpolar North Atlantic SST, known as the warming hole. The associated oceanic fingerprint matches with the observations over the last 15 years, where an intensification and cooling of the eastern SPG is related to salinity reduction at the eastern side of the SPG. However, for further warming beyond 2 K, in spite of a continuous decline in the AMOC, a northward shift of the mean zonal wind extends the subtropical gyre northward with an associated disruption of the eastern SPG intensification, resulting in the cessation of the warming hole. Therefore, a shift from the initially dominating oceanic drivers to the atmospheric driver results into a two-phase evolution of the North Atlantic Ocean SPG circulation and the associated SST under continuous global warming.

Tropical Instability Waves (TIWs) at the equatorial Atlantic Ocean lead to SST cooling due to enhanced mixing and heat fluxes above the EUC core. This phenomenon has been studied predominantly at the equator and to the north, where TIWs are most pronounced. However, a recent study has shown the presence of subsurface TIWs in the Atlantic Ocean, which frequently occur to the south of the equator. As TIW induced subsurface mixing leads to SST cooling at the equator, we suspect a similar cooling may occur in the Southern Hemisphere due to the presence of subsurface TIWs. Using one decade of high-resolution ICON ocean simulations, we investigate such effect of subsurface TIWs in the southern hemisphere on SST in the tropical Atlantic Ocean. The analysis of all terms of the mixed layer heat budget allows for the investigation and quantification of the processes involved in subsurface TIW induced SST changes.

We use reanalysis data to substantiate the role of Ural Blocking (UB) in driving the Warm Arctic‐Cold Siberia (WACS) pattern, which represents an anti‐correlation of surface temperature between the Barents‐Kara Seas and Central Asia. We confirm a robust link between UB and the WACS pattern on daily to sub‐seasonal timescales. UB controls the pace of the WACS; warming over the Barents‐Kara Seas and cooling over Central Asia peak 3‐5 days after the UB onset. The observed sea‐ice deficit over the Barents‐Kara Seas in the weeks prior to UB onset is not statistically significant when the long‐term trend in sea‐ice is removed. Thus, the sea‐ice deficit may not have a direct impact on UB occurrence but it develops as a delayed response to UB. The interannual variability of WACS is also strongly linked to UB. We identify an upward trend in wintertime UB in recent decades that accounts for a cooling rate of 1∘C/decade over Central Asia. Over the Barents‐Kara Seas, UB trends explain a small fraction of the warming, which is dominated by Arctic Amplification. Finally, the link between UB and the WACS is statistically robust over the ERA‐Interim period but weaker during the 1990s when the lowest activity of UB Episodes was observed.

The current warming of the oceans has been shown to have detrimental effects for a number of species. The understanding of the underlying mechanisms may be hampered by the non-linearity and non-stationarity of the relationships between temperature and demography, and by the insufficient length of available time series. Most demographic time series are too short to study the effect of climate on wildlife in the classical sense of meteorological patterns over at least 30 years. Here we present a harvest time series of Atlantic puffins (Fratercula arctica) that goes back as far as 1880. It originates in the world’s largest puffin colony, in southwest Iceland, which has recently experienced a strong decline. By estimating an annual chick production index for 128 years, we find prolonged periods of strong correlations between local sea surface temperature (SST) and chick production. The sign of decennial correlations switches three times during this period, where the phases of strong negative correlation between puffin productivity and SST correspond to the early 20th century Arctic warming period and to the most recent decades. Based on a shorter time series, one might have concluded that the correlation was uniformly negative or positive, or even absent. Most of the variation (72%) in chick production is explained by a model in which productivity peaks at an SST of 7.1 °C, clearly rejecting the assumption of a linear relationship. The SST at which the puffins’ production peaked has increased by 0.24 °C during the 20th century, although the increase in average SST during the same period has been more than three times faster. The best supported models indicate that the population’s decline is at least partially caused by the increasing SST around Iceland.

Tropical instability waves (TIWs) near the ocean surface are present in all tropical oceans and are known to be important for air-sea interactions and regional climate variability. Recent studies based on observations in the Pacific Ocean found that apart from TIWs at the surface, there also exist subsurface TIWs (subTIWs) which can alter vertical mixing. To date, most studies have focused on TIW related dynamics near the ocean surface. However, to properly assess vertical mixing in the upper ocean, improved understanding of the vertical structure of TIWs and the influence of subTIWs is needed. In this study, we show subTIW presence in the Atlantic Ocean for the first time using mooring observations.Further, we characterize subTIWs in the tropical Atlantic Ocean with a special focus on subTIW spatial and temporal variability and their effect on mixing. For this, data covering almost two decades are used that were generated from a comprehensive, global, high-resolution ocean model forced by the reanalysis ERA5. We find subTIWs between 40 m depth and the thermocline in both model and observations and unlike TIWs, subTIWs are frequently active both north and south of the Equator. The results of our study suggest that subTIWs induce a multi-layer shear structure which has the potential to destabilize the mean flow and thereby cause mixing. These effects are strongest north of the Equator where TIWs and subTIWs act simultaneously, implying possible TIW/subTIW interactions. We conclude that subTIWs are a feature of the tropical Atlantic Ocean with regionally varying implications for vertical mixing and heat fluxes. In addition, subTIWs differ from TIWs in their temporal and regional occurrences Therefore, subTIWs should be considered in future assessments of upper ocean dynamics, particularly in subTIW dominated regions.

Reconstructions of the global mean annual temperature evolution during the Holocene yield conflicting results. One temperature reconstruction shows global cooling during the late Holocene. The other reconstruction reveals global warming. Here we show that both a global warming mode and a cooling mode emerge when performing a spatio-temporal analysis of annual temperature variability during the Holocene using data from a transient climate model simulation. The warming mode is most pronounced in the tropics. The simulated cooling mode is determined by changes in the seasonal cycle of Arctic sea-ice that are forced by orbital variations and volcanic eruptions. The warming mode dominates in the mid-Holocene, whereas the cooling mode takes over in the late Holocene. The weighted sum of the two modes yields the simulated global temperature trend evolution. Our findings have strong implications for the interpretation of proxy data and the selection of proxy locations to compute global mean temperatures., Proxy reconstructions show a decreasing trend from the Middle to Late Holocene, which conflicts with model results showing an increasing trend. Statistical analysis of model output shows that these conflicting results originate from two distinct modes of variability, which dominate at different regions and times.

The question, whether ocean dynamics are relevant for basin-scale North Atlantic decadal temperature variability is subject of ongoing discussions. Here, we analyze a set of simulations with a single climate model, consisting of a 2000-year pre-industrial control experiment, a 100-member historical ensemble, and a 100-member ensemble forced with an incremental CO2 increase by 1%/year. Compared to previous approaches, our setup offers the following advantages: First, the large ensemble size allows to robustly separate internally and externally forced variability and to robustly detect statistical links between different quantities. Second, the availability of different scenarios allows to investigate the role of the background state for drivers of thevariability. We find strong evidence that ocean dynamics, particularly ocean heat transport variations, form an important contribution to generate the Atlantic Multidecadal Variability (AMV) in the Max Planck Institute Earth System Model (MPI- ESM). Particularly the Northwest North Atlantic is substantially affected by ocean circulation for the historical and pre-industrial simulations. Anomalies of the Labrador Sea deep ocean density precede a change of the Atlantic Meridional Overturning Circulation (AMOC) and heat advection to the region south of Greenland.Under strong CO2 forcing the AMV-SST regression pattern shows crucial changes: SST variability in the north western part of the North Atlantic is strongly reduced, so that the AMV pattern in this scenario is dominated by the low-latitude branch. We found a connection to changes in the deep water formation, that cause a strong reduction of the mean AMOC and its variability. Consequently, ocean heat transport convergence becomes less important for the SST variability south of Greenland.

This study investigates the dynamics that led to the repeated cold surges over midlatitude Eurasia, exceptionally warm conditions and sea ice loss over the Arctic, and the unseasonable weakening of the stratospheric polar vortex in autumn and early winter 2016-2017. We use ERA-Interim reanalysis data and COBE sea ice and sea surface temperature observational data to trace the dynamical pathways that caused these extreme phenomena. Following abnormally low sea ice conditions in early autumn over the Pacific sector of the Arctic basin, blocking anticyclones became dominant over Eurasia throughout autumn. Ural blocking (UB) activity was four times above climatological levels and organized in several successive events. UB episodes played a key role in the unprecedented sea ice loss observed in late autumn 2016 over the Barents-Kara Seas and the weakening of the stratospheric vortex. Each blocking induced circulation anomalies that resulted in cold air advection to its south and warm advection to its north. The near-surface warming anomalies over the Arctic and cooling anomalies over midlatitude Eurasia varied in phase with the life cycles of UB episodes. The sea ice cover minimum over the Barents-Kara Seas in 2016 was not observed in late summer but rather in mid-November and December shortly after the two strongest UB episodes. Each UB episode drove intense upward flux of wave activity that resulted in unseasonable weakening of the stratospheric vortex in November. The surface impact of this weakening can be linked to the migration of blocking activity and cold spells toward Europe in early winter 2017.

Proteasome inhibitors (PI) have evolved as the central backbone of treatment for multiple myeloma (MM), with first-in-class bortezomib and second- and third-generation PI, carfilzomib and ixazomib, having been approved for this indication. Proteasome inhibition disrupts the unfolded protein response to resolve excessive endoplasmic reticulum stress, but also leads to massive metabolic changes manifested by the induction of amino acid biosynthesis, an anti-oxidant response, lipogenesis and an increase in protein folding. In this sense, PI represent a unique class of drugs targeting cancer cell metabolism by affecting the balance between protein biosynthesis, folding and destruction. However, the adaptive changes in MM cell metabolism may provide the basis of resistance to PI, as high glycolytic activity or rewiring glucose metabolism is associated with bortezomib resistance in MM.

Precipitation and circulation patterns of Northern Hemisphere monsoons are investigated in Coupled Model Intercomparison Project phase 5 simulations for mid-Holocene and future climate scenario rcp8.5. Although both climates exhibit Northern Hemisphere warming and enhanced interhemispheric thermal contrast in boreal summer, changes in the spatial extent and rainfall intensity in future climate are smaller than in mid-Holocene for all Northern Hemisphere monsoons except the Indian monsoon. A decomposition of the moisture budget in thermodynamic and dynamic contributions suggests that under future global warming, the weaker response of the African, Indian, and North American monsoons results from a compensation between both components. The dynamic component, primarily constrained by changes in net energy input over land, determines instead most of the mid-Holocene land monsoonal rainfall response. ©2019. American Geophysical Union. All Rights Reserved.

Beside its global effects, climate change is manifested in many regionally pronounced features mainly resulting from changes in the oceanic and atmospheric circulation. Here we investigate the influence of the North Atlantic SST on shaping the winter-time response to global warming. Our results are based on a long-term climate projection with the Max Planck Institute Earth System Model (MPI-ESM) to investigate the influence of North Atlantic sea surface temperature pattern changes on shaping the atmospheric climate change signal. In sensitivity experiments with the model’s atmospheric component we decompose the response into components controlled by the local SST structure and components controlled by global/remote changes. MPI-ESM simulates a global warming response in SST similar to other climate models: there is a warming minimum—or ”warming hole”—in the subpolar North Atlantic, and the sharp SST gradients associated with the Gulf Stream and the North Atlantic Current shift northward by a few a degrees. Over the warming hole, global warming causes a relatively weak increase in rainfall. Beyond this, our experiments show more localized effects, likely resulting from future SST gradient changes in the North Atlantic. This includes a significant precipitation decrease to the south of the Gulf Stream despite increased underlying SSTs. Since this region is characterised by a strong band of precipitation in the current climate, this is contrary to the usual case that wet regions become wetter and dry regions become drier in a warmer climate. A moisture budget analysis identifies a complex interplay of various processes in the region of modified SST gradients: reduced surface winds cause a decrease in evaporation; and thermodynamic, modified atmospheric eddy transports, and coastal processes cause a change in the moisture convergence. The changes in the the North Atlantic storm track are mainly controlled by the non-regional changes in the forcing. The impact of the local SST pattern changes on regions outside the North Atlantic is small in our setup. © 2018 The Author(s)

International audience; the accumulation of magma within the Monti Sabatini Volcanic District (MSVD), italy, coupled with the extensional tectonics of the region, pose both volcanic and tectonic hazards to the city of Rome, located 20 km to the southeast. We combine 40 Ar/ 39 Ar geochronology of volcanic deposits and a geomorphologic/stratigraphic/paleomagnetic study of fluvial terraces to determine the recurrence interval and the time elapsed since the last eruption of the MSVD. Moreover, we provide a date for the youngest known eruption of the MSVD and assess the timing of the most recent volcanic phase. Results of this study show: (i) The most recent eruptive phase occurred between 100 ka and 70 ka; (ii) the anomalously high elevation of the MIS 5 terrace indicates that it was concurrent with 50 m of uplift in the volcanic area; (iii) the time since the last eruption (70 ka) exceeds the average recurrence interval (39 ky) in the last 300 ky, as well as the longest previous dormancy (50 ky) in that time span. (iv) the current duration of dormancy is similar to the timespan separating the major explosive phase that occurred 590-450 ka. The magnitude and patterns of deformation of a volcanic field provide constraints on the magmatic processes operating beneath a volcano. A recent geomorphological study 1 reconstructed a series of paleo-surfaces along a 40-km-long stretch of the Tiber River Valley north of Rome, between Magliano Sabina and Monterotondo, located at the eastern margin of the Monti Sabatini Volcanic District (MSVD) (Fig. 1a). These paleo-surfaces are interpreted as fluvial terraces formed through the interplay between regional uplift and glacio-eustasy (e.g. 2) during a regressive phase that formed the hydrographic network of the Paleo-Tiber River since the end of the Santernian (1.78-1.5 Ma; lower Calabrian) 3. The reconstructed rates of uplift during the last 1.8 Ma recognized two major pulses: 0.86 through 0.5 Ma, and 0.25 Ma through the present time 1. The coincidence of the uplift pulses with the ages of the main volcanic phases 1 are interpreted as mainly driven by uprising magma bodies from a metasomatized mantle source of the Roman Magmatic Province (e.g. 4-6). This "magmatic" uplift overlaps a smaller isostatic component on the Tyrrhenian Sea Margin of central Italy. In the present study, we further refine the chronostratigraphy of the paleo-surfaces in the area previously investigated, providing five new 40 Ar/ 39 Ar age determinations on volcanic products intercalated within the

Downregulation of the unfolded protein response mediates proteasome inhibitor resistance in multiple myeloma. The Human Immunodeficieny Virus protease inhibitor nelfinavir activates the unfolded protein response in vitro. We determined dose-limiting toxicity and recommended dose for phase II of nelfinavir in combination with the proteasome inhibitor bortezomib. Twelve patients with advanced hematologic malignancies were treated with nelfinavir (2500-5000 mg/day p.o., days 1-14, 3+3 dose escalation) and bortezomib (1.3 mg/m(2), days 1, 4, 8, 11; 21-day cycles). A run in phase with nelfinavir monotherapy allowed pharmakokinetic/pharmakodynamic assessment of nelfinavir in the presence or absence of concomittant bortezomib. End points included dose-limiting toxicity, activation of the unfolded protein response, proteasome activity, toxicity and response to trial treatment. Nelfinavir 2×2500 mg was the recommended phase II dose identified. Nelfinavir alone significantly up-regulated expression of proteins related to the unfolded protein response in peripheral blood mononuclear cells and inhibited proteasome activity. Of 10 evaluable patients in the dose escalation cohort, 3 achieved a partial response, 4 stable disease for 2 cycles or more, while 3 had progressive disease as best response. In an exploratory extension cohort with 6 relapsed, bortezomib-refractory, lenalidomide-resistant myeloma patients treated at the recommended phase II dose, 3 reached a partial response, 2 a minor response, and one progressive disease. The combination of nelfinavir with bortezomib is safe and shows promising activity in advanced, bortezomib-refractory multiple myeloma. Induction of the unfolded protein response by nelfinavir may overcome the biological features of proteasome inhibitor resistance. (clinicaltrials.gov identifier: 01164709).

Proteasome inhibitors (PIs) are a backbone of multiple myeloma (MM) therapy. The proteasome harbors six proteolytically active subunits (β1, β2, β5), while β5 was identified as rate-limiting and is a primary target of clinically available PIs. The most effective pattern of subunit inhibition provided by these PIs for cytotoxic activity in MM is unknown. A head-to-head comparison of clinically available PIs shows that in the clinically relevant setting only the co-inhibition of β1 or β2 with β5 activity achieves meaningful functional proteasome inhibition and cytotoxicity, while the selective β2/β5 inhibition of both constitutive and immunoproteasome is the most cytotoxic. In the long-term setting, selective inhibition of β5 subunit is sufficient to induce cytotoxicity in PI-sensitive, but not in PI-resistant MM, and the β5/β2 co-inhibition is the most cytotoxic in PI-resistant MM. These results give a rational basis for selecting individual PIs for the treatment of MM.

A new release of the Max Planck Institute for Meteorology Earth System Model version 1.2 (MPI‐ESM1.2) is presented. The development focused on correcting errors in and improving the physical processes representation, as well as improving the computational performance, versatility, and overall user friendliness. In addition to new radiation and aerosol parameterizations of the atmosphere, several relatively large, but partly compensating, coding errors in the model's cloud, convection, and turbulence parameterizations were corrected. The representation of land processes was refined by introducing a multilayer soil hydrology scheme, extending the land biogeochemistry to include the nitrogen cycle, replacing the soil and litter decomposition model and improving the representation of wildfires. The ocean biogeochemistry now represents cyanobacteria prognostically in order to capture the response of nitrogen fixation to changing climate conditions and further includes improved detritus settling and numerous other refinements. As something new, in addition to limiting drift and minimizing certain biases, the instrumental record warming was explicitly taken into account during the tuning process. To this end, a very high climate sensitivity of around 7 K caused by low‐level clouds in the tropics as found in an intermediate model version was addressed, as it was not deemed possible to match observed warming otherwise. As a result, the model has a climate sensitivity to a doubling of CO2 over preindustrial conditions of 2.77 K, maintaining the previously identified highly nonlinear global mean response to increasing CO2 forcing, which nonetheless can be represented by a simple two‐layer model., Key Points An updated version of the Max Planck Institute for Meteorology Earth System Model (MPI‐ESM1.2) is presentedThe model includes both code corrections and parameterization improvementsDespite this, the model maintains an equilibrium climate sensitivity, which rises with warming

Proteasome inhibitor (PI) carfilzomib (CFZ) has activity superior to bortezomib (BTZ) and is increasingly incorporated in multiple myeloma (MM) frontline therapy and relapsed settings. Most MM patients ultimately experience PI-refractory disease, an unmet medical need with poorly understood biology and dismal outcome. Pharmacologic targeting of ABCB1 improved patient outcomes, including MM, but suffered from adverse drug effects and insufficient plasma concentrations. Proteomics analysis identified ABCB1 overexpression as the most significant change in CFZ-resistant MM cells. We addressed the functional role of ABCB1 overexpression in MM and observed significantly upregulated ABCB1 in peripheral blood malignant plasma cells (PCs) vs untreated patients' bone marrow PC. ABCB1 overexpression reduces the proteasome-inhibiting activity of CFZ due to drug efflux, in contrast to BTZ. Likewise, the cytotoxicity of established anti-MM drugs was significantly reduced in ABCB1-expressing MM cells. In search for potential drugs targeting ABCB1 in clinical trials, we identified the HIV protease inhibitors nelfinavir (NFV) and lopinavir (LPV) as potent functional modulators of ABCB1-mediated drug export, most likely via modulation of mitochondria permeability transition pore. NFV and LPV restored CFZ activity at therapeutically relevant drug levels and thus represent ready-to-use drugs to be tested in clinical trials to target ABCB1 and to re-sensitize PC to established myeloma drugs, in particular CFZ.

Despite a substantial hemispheric asymmetry in clear-sky albedo, observations of Earth’s radiation budget reveal that the two hemispheres have the same all-sky albedo. Here, aquaplanet simulations with the atmosphere general circulation model ECHAM6 coupled to a slab ocean are performed to study to what extent and by which mechanisms clouds compensate hemispheric asymmetries in clear-sky albedo. Clouds adapt to compensate the imposed asymmetries because the intertropical convergence zone (ITCZ) shifts into the dark surface hemisphere. The strength of this tropical compensation mechanism is linked to the magnitude of the ITCZ shift. In some cases the ITCZ shift is so strong as to overcompensate the hemispheric asymmetry in clear-sky albedo, yielding a range of climates for which the hemisphere with lower clear-sky albedo has a higher all-sky albedo. The ITCZ shift is sensitive to the convection scheme and the depth of the slab ocean. Cloud–radiative feedbacks explain part of the sensitivity to the convection scheme as they amplify the ITCZ shift in the Tiedtke (TTT) scheme but have a neutral effect in the Nordeng (TNT) scheme. A shallower slab ocean depth, and thereby reduced thermal inertia of the underlying surface and increased seasonal cycle, stabilizes the ITCZ against annual-mean shifts. The results lend support to the idea that the climate system adjusts so as to minimize hemispheric albedo asymmetries, although there is no indication that the hemispheres must have exactly the same albedo.

International audience; This paper introduces the Tropical Rain belts with an Annual cycle and a Continent Model Inter-comparison Project (TRACMIP). TRACMIP studies the dynamics of tropical rain belts and their response to past and future radiative forcings through simulations with 13 comprehensive and one simplified atmosphere models coupled to a slab ocean and driven by seasonally varying insolation. Five idealized experiments , two with an aquaplanet setup and three with a setup with an idealized tropical continent, fill the space between prescribed-SST aquaplanet simulations and realistic simulations provided by CMIP5/6. The simulations reproduce key features of present-day climate and expected future climate change, including an annual-mean intertropical convergence zone (ITCZ) that is located north of the equator and Hadley cells and eddy-driven jets that are similar to present-day climate. Quadrupling CO2 leads to a northward ITCZ shift and preferential warming in Northern high latitudes. The simulations show interesting CO2-induced changes in the seasonal excursion of the ITCZ and indicate a possible state dependence of climate sensitivity. The inclusion of an idealized continent modulates both the control climate and the response to increased CO2 ; for example, it reduces the northward ITCZ shift associated with warming and, in some models , climate sensitivity. In response to eccentricity-driven seasonal insolation changes, seasonal changes in oceanic rainfall are best characterized as a meridional dipole, while seasonal continental rainfall changes tend to be symmetric about the equator. This survey illustrates TRACMIP's potential to engender a deeper understanding of global and regional climate and to address questions on past and future climate change.

The bio-physical feedback process between the marine ecosystem and the tropical climate system is investigated using both an ocean circulation model and a fully-coupled ocean–atmosphere circulation model, which interact with a biogeochemical model. We found that the presence of chlorophyll can have significant impact on the characteristics of the El Nino-Southern Oscillation (ENSO), including its amplitude and asymmetry, as well as on the mean state. That is, chlorophyll generally increases mean sea surface temperature (SST) due to the direct biological heating. However, SST in the eastern equatorial Pacific decreases due to the stronger indirect dynamical response to the biological effects outweighing the direct thermal response. It is demonstrated that this biologically-induced SST cooling is intensified and conveyed to other tropical-ocean basins when atmosphere–ocean coupling is taken into account. It is also found that the presence of chlorophyll affects the magnitude of ENSO by two different mechanisms; one is an amplifying effect by the mean chlorophyll, which is associated with shoaling of the mean thermocline depth, and the other is a damping effect derived from the interactively-varying chlorophyll coupled with the physical model. The atmosphere–ocean coupling reduces the biologically-induced ENSO amplifying effect through the weakening of atmospheric feedback. Lastly, there is also a biological impact on ENSO which enhances the positive skewness. This skewness change is presumably caused by the phase dependency of thermocline feedback which affects the ENSO magnitude.

There is evidence that the observed changes in winter North Atlantic Oscillation (NAO) drive a significant portion of Atlantic Multi Decadal Variability (AMV). However, whether the observed decadal NAO changes can be forced by the ocean is controversial. There is also evidence that artificially imposed multi-decadal stratospheric changes can impact the troposphere in winter. But the origins of such stratospheric changes are still unclear, especially in early to mid winter, where the radiative ozone-impact is negligible. Here we show, through observational analysis and atmospheric model experiments, that large-scale Atlantic warming associated with AMV drives high-latitude precursory stratospheric warming in early to mid winter that propagates downward resulting in a negative tropospheric NAO in late winter. The mechanism involves stratosphere/troposphere dynamical coupling, and can be simulated to a large extent, but only with a stratosphere resolving model (i.e., high-top). Further analysis shows that this precursory stratospheric response can be explained by the shift of the daily extremes toward more major stratospheric warming events. This shift cannot be simulated with the atmospheric (low-top) model configuration that poorly resolves the stratosphere and implements a sponge layer in upper model levels. While the potential role of the stratosphere in multi-decadal NAO and Atlantic meridional overturning circulation changes has been recognised, our results show that the stratosphere is an essential element of extra-tropical atmospheric response to ocean variability. Our findings suggest that the use of stratosphere resolving models should improve the simulation, prediction, and projection of extra-tropical climate, and lead to a better understanding of natural and anthropogenic climate change.

[1] ECHAM6, the sixth generation of the atmospheric general circulation model ECHAM, is described. Major changes with respect to its predecessor affect the representation of shortwave radiative transfer, the height of the model top. Minor changes have been made to model tuning and convective triggering. Several model configurations, differing in horizontal and vertical resolution, are compared. As horizontal resolution is increased beyond T63, the simulated climate improves but changes are incremental; major biases appear to be limited by the parameterization of small-scale physical processes, such as clouds and convection. Higher vertical resolution in the middle atmosphere leads to a systematic reduction in temperature biases in the upper troposphere, and a better representation of the middle atmosphere and its modes of variability. ECHAM6 represents the present climate as well as, or better than, its predecessor. The most marked improvements are evident in the circulation of the extratropics. ECHAM6 continues to have a good representation of tropical variability. A number of biases, however, remain. These include a poor representation of low-level clouds, systematic shifts in major precipitation features, biases in the partitioning of precipitation between land and sea (particularly in the tropics), and midlatitude jets that appear to be insufficiently poleward. The response of ECHAM6 to increasing concentrations of greenhouse gases is similar to that of ECHAM5. The equilibrium climate sensitivity of the mixed-resolution (T63L95) configuration is between 2.9 and 3.4 K and is somewhat larger for the 47 level model. Cloud feedbacks and adjustments contribute positively to warming from increasing greenhouse gases.

We investigate how differently-constructed indices for North Atlantic sea-surface temperatures (NASSTs) describe the “Atlantic Multidecadal Variability” (AMV) in a suite of unperturbed as well as externally-forced millennial (pre-industrial period) climate simulations. The simulations stem from an ensemble of Earth system models differing in both resolution and complexity. Different criteria exist to construct AMV indices capturing different aspects of the phenomenon. Although all representations of the AMV maintain strong multidecadal variability, they depict different characteristics of simulated low-frequency NASST variability, evolve differently in time and relate to different hemispheric teleconnections. Due to such multifaceted signatures in the ocean-surface as well as in the atmosphere, reconstructions of past AMV may not univocally reproduce multidecadal NASST variability. AMV features under simulated externally-forced pre-industrial climate conditions are not unambiguously distinguishable, within a linear framework, from AMV features in corresponding unperturbed simulations. This prevents a robust diagnosis of the simulated pre-industrial AMV as a predominantly internal rather than externally-forced phenomenon. We conclude that a multi-perspective assessment of multidecadal NASSTs variability is necessary for understanding the origin of the AMV, its physics and its climatic implications.

The instrumental records indicate that the basin-wide wintertime North Atlantic warm conditions are accompanied by a pattern resembling negative North Atlantic oscillation (NAO), and cold conditions with pattern resembling the positive NAO. This relation is well reproduced in a control simulation by the stratosphere resolving atmosphere–ocean coupled Max-Planck-Institute Earth System Model (MPI-ESM). Further analyses of the MPI-ESM model simulation shows that the large-scale warm North Atlantic conditions are associated with a stratospheric precursory signal that propagates down into the troposphere, preceding the wintertime negative NAO. Additional experiments using only the atmospheric component of MPI-ESM (ECHAM6) indicate that these stratospheric and tropospheric changes are forced by the warm North Atlantic conditions. The basin-wide warming excites a wave-induced stratospheric vortex weakening, stratosphere/troposphere coupling and a high-latitude tropospheric warming. The induced high-latitude tropospheric warming is associated with reduction of the growth rate of low-level baroclinic waves over the North Atlantic region, contributing to the negative NAO pattern. For the cold North Atlantic conditions, the strengthening of the westerlies in the coupled model is confined to the troposphere and lower stratosphere. Comparing the coupled and uncoupled model shows that in the cold phase the tropospheric changes seen in the coupled model are not well reproduced by the standalone atmospheric configuration. Our experiments provide further evidence that North Atlantic Ocean variability (NAV) impacts the coupled stratosphere/troposphere system. As NAV has been shown to be predictable on seasonal-to-decadal timescales, these results have important implications for the predictability of the extra-tropical atmospheric circulation on these time-scales

We investigate the strong warm bias in sea surface temperatures (SST) of the southeastern tropical Atlantic that occurs in most of the current global climate models. We analyse this bias in the Max Planck Institute Earth System Model at different horizontal resolutions ranging from 0.1° to 0.4° in the ocean and 0.5° to 1.8° in the atmosphere. High atmospheric horizontal resolution eliminates the SST bias close to the African coast, due to an improved representation of surface wind-stress near the coast. This improvement affects coastal upwelling and horizontal ocean circulation, as confirmed with dedicated sensitivity experiments. The wind-stress improvements are partly caused by the better represented orography at higher horizontal resolution in the spectral atmospheric model. The reductions of the coastal SST bias obtained through higher horizontal resolution do not, however, translate to a reduction of the large-scale bias extending westward from the African coast into the southeastern tropical Atlantic.

Adaptive resistance of myeloma to proteasome inhibition represents a clinical challenge, whose biology is poorly understood. Proteasome mutations were implicated as underlying mechanism, while an alternative hypothesis based on low activation status of the unfolded protein response was recently suggested (IRE1/XBP1-low model). We generated bortezomib- and carfilzomib-adapted, highly resistant multiple myeloma cell clones (AMO-BTZ, AMO-CFZ), which we analyzed in a combined quantitative and functional proteomic approach. We demonstrate that proteasome inhibitor-adapted myeloma cells tolerate subtotal proteasome inhibition, irrespective of a proteasome mutation, and uniformly show an 'IRE1/XBP1-low' signature. Adaptation of myeloma cells to proteasome inhibitors involved quantitative changes in >600 protein species with similar patterns in AMO-BTZ and AMO-CFZ cells: proteins involved in metabolic regulation, redox homeostasis, and protein folding and destruction were upregulated, while apoptosis and transcription/translation were downregulated. The quantitatively most upregulated protein in AMO-CFZ cells was the multidrug resistance protein (MDR1) protein ABCB1, and carfilzomib resistance could be overcome by MDR1 inhibition. We propose a model where proteasome inhibitor-adapted myeloma cells tolerate subtotal proteasome inhibition owing to metabolic adaptations that favor the generation of reducing equivalents, such as NADPH, which is supported by oxidative glycolysis. Proteasome inhibitor resistance may thus be targeted by manipulating the energy and redox metabolism.

Several studies have analysed the atmospheric response to sea-ice changes in the Arctic region, but only few have considered the Antarctic. Here, the atmospheric response to sea-ice variability in the Southern Hemisphere is investigated with the atmospheric general circulation model ECHAM5. The model is forced by the present and a projected future seasonal cycle of Antarctic sea ice. In September, the mean atmospheric response exhibits distinct similarities to the structure of the negative phase of the Southern Annular Mode, the leading mode of Southern Hemisphere variability. In the reduced Antarctic sea-ice integration, there is an equatorward shift of the Southern Hemisphere mid-latitude jet and the storm tracks. In contrast to a recent previous study, our findings indicate that a substantial impact of Southern Hemispheric future sea-ice reduction on the mid-latitude circulation cannot be ruled out. © 2012 Springer-Verlag.

The Arctic has undergone substantial changes over the last few decades in various cryospheric and derivative systems and processes. Of these, the Arctic sea ice regime has seen some of the most rapid change and is one of the most visible markers of Arctic change outside the scientific community. This has drawn considerable attention not only from the natural sciences, but increasingly, from the political and commercial sectors as they begin to grapple with the problems and opportunities that are being presented. The possible impacts of past and projected changes in Arctic sea ice, especially as it relates to climatic response, are of particular interest and have been the subject of increasing research activity. A review of the current knowledge of the role of sea ice in the climate system is therefore timely. We present a review that examines both the current state of understanding, as regards the impacts of sea-ice loss observed to date, and climate model projections, to highlight hypothesised future changes and impacts on storm tracks and the North Atlantic Oscillation. Within the broad climate-system perspective, the topics of storminess and large-scale variability will be specifically considered. We then consider larger-scale impacts on the climatic system by reviewing studies that have focused on the interaction between sea-ice extent and the North Atlantic Oscillation. Finally, an overview of the representation of these topics in the literature in the context of IPCC climate projections is presented. While most agree on the direction of Arctic sea-ice change, the rates amongst the various projections vary greatly. Similarly, the response of storm tracks and climate variability are uncertain, exacerbated possibly by the influence of other factors. A variety of scientific papers on the relationship between sea-ice changes and atmospheric variability have brought to light important aspects of this complex topic. Examples are an overall reduction in the number of Arctic winter storms, a northward shift of mid-latitude winter storms in the Pacific and a delayed negative NAO-like response in autumn/winter to a reduced Arctic sea-ice cover (at least in some months). This review paper discusses this research and the disagreements, bringing about a fresh perspective on this issue. Highlights: ► Observed decrease in sea-ice extent is faster than predicted. ► September sea ice reaching record low in recent years. ► Reduction in the number of Arctic winter storms. ► Northward shift of midlatitude storms and uncertainty over changes in intensity. ► Most models simulate a negative NAO response when forced with less Arctic sea-ice.

Purpose Proteasome-inhibiting drugs (PI) are gaining importance in hematologic oncology. The proteasome carries three proteolytically active subunits (β1, β2, β5). All established PI (bortezomib and carfilzomib), as well as experimental drugs in the field (dalanzomib, oprozomib, and ixazomib), by design target the rate-limiting β5 subunit. It is unknown whether β2-selective proteasome inhibition can also be exploited toward anticancer treatment. Combining PI with the pan B-cell-directed Bruton tyrosine kinase inhibitor ibrutinib appears a natural option for future improved treatment of multiple myeloma (MM) and B-cell lymphomas. However, bortezomib induces phosphorylation of IκB and activation of NF-κB in MM cells, while ibrutinib inhibits the IκB/NF-κB axis, suggesting antagonistic signaling. A β2-selective proteasome inhibitor may lack such antagonistic signaling effects. Methods We recently introduced LU-102, the first β2-selective PI available for preclinical testing. We here compare bortezomib with carfilzomib and LU-102 in MM and MCL in vitro with regard to their effects on pIκB/NF-κB signaling and their cytotoxic activity in combination with ibrutinib. Results LU-102 reduced phosphorylation of IκB, in contrast to bortezomib and carfilzomib, and was a superior inhibitor of NF-κB activation in MM cells. This translated into highly synergistic cytotoxicity between LU-102 and ibrutinib, which was able to overcome BTZ resistance and CFZ resistance. By contrast, BTZ lacked consistent synergistic cytotoxicity with ibrutinib. Conclusion Ibrutinib is highly synergistic with β2-selective proteasome inhibition against MM and MCL in vitro. Novel β2-selective proteasome inhibitors may be exploited to overcome bortezomib/carfilzomib resistance and boost the activity of BTK inhibitors against B-cell-derived malignancies.

Phytoplankton have attracted increasing attention in climate science due to their impacts on climate systems. A new generation of climate models can now provide estimates of future climate change, considering the biological feedbacks through the development of the coupled physical–ecosystem model. Here we present the geophysical impact of phytoplankton, which is often overlooked in future climate projections. A suite of future warming experiments using a fully coupled ocean−atmosphere model that interacts with a marine ecosystem model reveals that the future phytoplankton change influenced by greenhouse warming can amplify Arctic surface warming considerably. The warming-induced sea ice melting and the corresponding increase in shortwave radiation penetrating into the ocean both result in a longer phytoplankton growing season in the Arctic. In turn, the increase in Arctic phytoplankton warms the ocean surface layer through direct biological heating, triggering additional positive feedbacks in the Arctic, and consequently intensifying the Arctic warming further. Our results establish the presence of marine phytoplankton as an important potential driver of the future Arctic climate changes.

The first-in-class alkylating HDAC inhibitor EDO-S101 is highly synergistic with proteasome inhibition against multiple myeloma through activation of multiple pathways

Background Protein metabolism is an innovative potential therapeutic target for AML. Proteotoxic stress (PS) sensitizes malignant cells for proteasome inhibitor treatment. Some HIV protease inhibitors (HIV-PI) induce PS and may therefore be combined with proteasome inhibitors to achieve PS-targeted therapy of AML. Methods We investigated the effects of all nine approved HIV-PI alone and in combination with proteasome inhibitors on AML cell lines and primary cells in vitro. Results Ritonavir induced cytotoxicity and PS at clinically achievable concentrations, and induced synergistic PS-triggered apoptosis with bortezomib. Saquinavir, nelfinavir and lopinavir were likewise cytotoxic against primary AML cells, triggered PS-induced apoptosis, inhibited AKT-phosphorylation and showed synergistic cytotoxicity with bortezomib and carfilzomib at low micromolar concentrations. Exclusively nelfinavir inhibited intracellular proteasome activity, including the β2 proteasome activity that is not targeted by bortezomib/carfilzomib. Conclusions Of the nine currently approved HIV-PI, ritonavir, saquinavir, nelfinavir and lopinavir can sensitize AML primary cells for proteasome inhibitor treatment at low micromolar concentrations and may therefore be tested clinically toward a proteotoxic stress targeted therapy of AML.

Malignant plasma cells drive massive overproduction of monoclonal immunoglobulin in multiple myeloma (MM). Hence MM cells critically rely on a proper balance between protein biosynthesis and folding, and degradation of unfolded/ misfolded protein orchestrated by the unfolded protein response (UPR). Inhibitors of the proteasome, the terminal protease along the UPR pathway, are highly effective against MM. Adaptive resistance to current proteasome inhibitors (PI) (Bortezomib-Btz, Carfilzomib-Cfz) is a major cause of treatment failure. Btz is a peptide boronate-type reversible inhibitor, whereas Cfz is of epoxyketone-type and binds irreversibly to the same proteasomal B5 active site target. Next generation PI are likewise B5-directed and either of the peptide boronate (ixazomib, dalanzomib), or the epoxyketone type (oprozomib). PI resistance is currently understood via two alternative concepts, the load/capacity concept characterized by proteasome upregulation in conjunction with downregulation of the UPR via reduced IRE/XBP-1 signaling, and the mutation concept basing on B5 active site mutations that prevent PI binding. Only IRE1/XBP1 downregulation have been confirmed in patient-derived material. We generated an in vitro model where AMO-1 myeloma cells (IC50: 3.1nM for Btz, 4.9nM Cfz) were adapted to Btz (AMOaBtz; IC50: 298.7nM Btz, 43.2nM Cfz) or to Cfz, (AMOaCfz; IC50: 27.9nM Btz, 411.5nM Cfz). AMOaBtz cells showed preferential resistance against ixazomib and dalanzomib, while AMOaCfz cells were preferentially resistant to oprozomib and other epoxyketone-type experimental inhibitors. AMOaBtz and AMOaCfz likewise downregulated IRE/XBP-1, but only AMOaBtz contained an acquired proteasome mutation (A310G in PSMB5), however this had only a modest influence on Btz binding and proteasome inhibition. Global gene expression analysis revealed 1430 differentially expressed genes in AMOaBtz/ AMOaCfz (FC>2, p Citation Format: Andrej Besse, Lenka Besse, Marianne Kraus, Jurgen Bader, Mario Novkovic, Fedor Kryukov, Pavel Nemec, Tobias Silzle, Christoph Driessen. Inside of multiple mechanism of adaption towards the proteasome inhibitors in multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1243.

Background: EDO-S101 is a first-in-class alkylating histone-deacetylase inhibitor (HDACi) fusion molecule that combines the strong DNA damaging effect of bendamustine, with a fully functional pan-HDAC inhibitor, vorinostat. Bendamustine has substantial clinical activity against B-cell malignancies, lacks cross resistance with many other anticancer drugs, has superior antimyeloma activity compared to melphalan, and can safely be combined with proteasome inhibitors. The Histone deacetylase inhibitor (HDACi) vorinostat has a broad spectrum of epigenetic activities and sensitizes lymphoma and myeloma cells for a variety of cytotoxic drugs. Vorinostat in particular has a strong synergy with proteasome inhibitors, presumably due to the inhibition of HDAC6. HDAC6 allows polyubiquitinated substrate protein to bypass the inhibited proteasome towards degradation via the autophagy pathway. The EDO-S101 molecule was designed to create a very potent cytotoxic agent for systemic use upon exploiting the synergies of a bi-functional mode of action. Methods: The aim of the in vitro study was to compare the cytotoxicity of EDO-S101 against Multiple Myeloma (MM), leukemia and lymphoma cells with established alkylating agents and to investigate its cellular and molecular effects in combination with proteasome inhibitors. Results: The IC50 of EDO-S101 ranged between 5-13 μM in 8 myeloma cell lines and thus one order of magnitude lower than the IC50 for bendamustine (70 - > 200 μM). Myeloma cell lines with adaptive resistance against bortezomib or carfilzomib did not differ from non-adapted cells in their IC50 for EDO-S101. Likewise, the IC50 for 3 ABC type DLBCL cell lines ranged between 3-8 μM for EDO-S101, compared to bendamustine > 50 μM. EDO-S101 had significant synergistic cytotoxicity with the proteasome inhibitors bortezomib and carfilzomib across all cell types tested, in contrast to melphalan and bendamustine. In a panel of 6 MM cell lines, the combination of EDO-S101 yielded a mean combination index for synergistic cytotoxicity of 0.12 (± 0.06) and 0.08 (± 0.06) for bortezomib or carfilzomib combinations, respectively (with values < 0.8 indicating significant synergism), in contrast to bendamustine 1.35 (± 0.87) and 1.29 (± 0.86), and melphalan 1.09 (± 0.66) and 1.20 (± 1.44). Likewise, EDO-S101 showed synergistic cytotoxicity with bortezomib and carfilzomib against mantle cell lymphoma cells (mean CIs 0.6 and 0.2), in contrast to bendamustine (CIs 1.72, 1.22) and melphalan (CIs 1.16 and 1.17), as well as ABC type DLBCL (CIs 0.32 and 0.28 for EDO S-101, compared to 15 and 34 for bendamustine and 0.87 and 0.78 for melphalan). To dissect the molecular mechanism for the unique synergistic cytotoxicity of EDO-S101 with proteasome inhibition, which contrasted to the established alkylating drugs, we analysed proteasome activity, protein acetylation status, accumulation of polyubiquitinated proteins as well as regulatory and effector proteins of the unfolded protein response (UPR) in RPMI8226 myeloma cells by western blot. EDO-S101 induced strong protein and histone acetylation, confirming its HDACi-like activity. Interestingly, and in contrast to bendamustine, melphalan and vorinostat, EDO-S101 was a strong inducer of pIRE-1, the key activator protein of the UPR in MM cells. IRE1 activation and induction of the UPR have recently been shown to be the major determinants of proteasome inhibitor sensitivity in human MM. Conclusions: We conclude that EDO-S101, an alkylating HDAC inhibitor fusion molecule, displays bi-functional activity. Compared to bendamustine and melphalan, it has superior monoactivity in vitro against hematologic malignancies including MM, mantle cell lymphoma and ABC type DLBCL. Of particular interest is the strong synergy of EDO-S101 with proteasome inhibitors which also stands out in comparison to the established alkylating agents. The latter is associated with induction of pIRE1, the key regulator of the UPR by EDO- S101. Both, the superior monoactivity of EDO-S101 and its mechanism-based synergy with proteasome inhibitors warrant further development of the compound towards clinical testing. Disclosures Driessen: Mundipharma: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Rationale: Overcoming proteasome inhibitor (PI) resistance is a challenge in multiple myeloma (MM) therapy since most MM patients ultimately develop PI resistance. Induction of excessive activation of the unfolded protein response (UPR) is the major mechanism of PI-induced cytotoxicity in MM. The UPR is a complex transcriptional response that balances biosynthesis, folding and proteasomal destruction of cellular protein. UPR inactivation results in PI resistance in vitro, and MM cells with low UPR activation accumulate and drive the relapse in PI-resistant MM patients. Pharmacologic activation of the UPR overcomes PI-resistance in preclinical models of MM and provides an option for clinical testing. The HIV protease inhibitor nelfinavir (NFV) has UPR-inducing activity via an unknown mechanism that may involve interference with regulatory proteases in the UPR and/or proteasome activity. NFV has single agent activity in MM and sensitizes MM and AML cells for PI treatment in vitro and in vivo. Methods: We performed a multicenter phase I dose escalation study to assess safety and recommended dose for phase II of NFV in combination with bortezomib (BTZ) in patients with advanced hematologic malignancies, and to detect signals for activity. NFV was given d 1-14 twice daily p.o. at the dose levels 1250 mg (DL0), 1875 mg (DL1) and 2500 mg (DL2), BTZ was dosed 1.3 mg/m2 d 1, 4, 8, 11 i.v. in 21 day cycles. The first treatment cycle was preceded by one week of NFV monotherapy for assessment of pharmacokinetic/pharmacodynamic parameters (NFV plasma concentrations, proteasome activity and expression of UPR-related proteins in peripheral blood mononuclear cells (PBMC)). Patients were treated for 3 cycles per protocol with the option to receive up to a total of 7 cycles. Results: 12 patients were treated in the dose escalation cohort (median age 58 years; 8 patients with MM, 1 each with ALL, AML, DLBCL, MCL) for an average of 2.6 cycles. All MM patients had received prior BTZ. DLT was determined in cycle 1 in which 93 % of planned dose was delivered. One DLT was observed (G4 ALT elevation at DL2 that spontaneously resolved). Toxicity was mostly mild, could be handled symptomatically, and did not lead to study drug discontinuation except for one case of thrombocytopenia. Diarrhoea G1-2 was the most frequent toxicity observed. Ten patients were evaluable for best response while on trial therapy after having received at least one full cycle. Of these, three patients achieved a PR (1 MCL, 2 MM), 4 remained in SD for at least 2 cycles (2 MM, 1 AML, 1 ALL), while 3 progressed (2 MM, 1 DLBCL). Peak NFV plasma concentrations during monotherapy were in the dose range putatively required for UPR activation, tended to be higher in patients treated at DL1, compared to DL2 (means 13.3 vs. 8.9 mM, p=0.08) and were significantly higher during NFV monotherapy than during combination therapy with BTZ (means 9.24 vs. 6.60 mM, p=0.04), suggesting induction of NFV clearance either by autoinduction, concomitant BTZ application, or both. Pharmacodynamic analysis revealed upregulation of proteins related to UPR-induced apoptosis by NFV monotherapy in PBMC (CHOP +56%, p=0.008; PARP +57%, p=0.04, n=10). Activity of the BTZ-insensitive proteasome b2 subunit in PBMC decreased (-16%, p=0.01) during NFV monotherapy, compared to baseline, as did the BTZ-sensitive b1/b5 subunit (-17%, p=0.001). To detect additional signals for activity, an extension cohort of 6 heavily pretreated MM patients that had shown BTZ-resistance during the past 12 months and were in addition lenalidomide-resistant was treated at the recommended dose (DL2). Three of these patients achieved a PR and 2 a MR, while 1 showed PD with a mean of 4.3 cycles administered. Overall, 12 MM patients could be evaluated for best response while on therapy with BTZ + NFV in this study, of which 5 achieved a paraprotein reduction of > 50% compared to baseline (figure 1). Conclusion: Nelfinavir 2500 mg p.o. twice daily induces UPR activation and proteasome inhibition. It can safely be combined with bortezomib (1.3 mg/m2 d 1, 4, 8, 11) to potentially increase bortezomib sensitivity of hematologic malignancies. The combination yields promising clinical activity signals in patients with bortezomib-resistant myeloma. Figure 1: Best paraprotein response, relative to baseline, of evaluable patients with relapsed-refractory myeloma treated with bortezomib + nelfinavir at any dose level for at least one full cycle. Figure 1:. Best paraprotein response, relative to baseline, of evaluable patients with relapsed-refractory myeloma treated with bortezomib + nelfinavir at any dose level for at least one full cycle. Disclosures Off Label Use: the presentation will include off label use of nelfinavir as investigational medicinal product (IMP). Hitz:Celgene: Research Funding.

The sea surface temperatures (SSTs) of the tropical Indian Ocean show a pronounced warming since the 1950s. We have analyzed the impact of this warming on Sahelian rainfall and on the North Atlantic Oscillation (NAO) by conducting ensemble experiments with an atmospheric general circulation model. Additionally, we investigate the impact of the other two tropical oceans on these two climate parameters. Our results suggest that the warming trend in the Indian Ocean played a crucial role for the drying trend over the West Sahel from the 1950s to 1990s and may also have contributed to the strengthening of the NAO during the most recent decades.

HIV protease inhibitors (HIV-PI) are oral drugs for HIV treatment. HIV-PI have antitumor activity via induction of ER-stress, inhibition of phospho-AKT (p-AKT) and the proteasome, suggesting antimyeloma activity. We characterize the effects of all approved HIV-PI on myeloma cells. HIV-PI were compared regarding cytotoxicity, proteasome activity, ER-stress induction and AKT phosphorylation using myeloma cells in vitro. Nelfinavir is the HIV-PI with highest cytotoxic activity against primary myeloma cells and with an IC50 near therapeutic drug blood levels (8–14 μM), irrespective of bortezomib sensitivity. Only nelfinavir inhibited intracellular proteasome activity in situ at drug concentrations

Abstract 4069 Background: HIV protease inhibitors (HIV-PI: Ritonavir, Lopinavir, Saquinavir, Nelfinavir, Amprenavir, Indinavir, Atazanavir, Tipranavir and Darunavir) are oral drugs approved for HIV treatment. Although designed to inhibit the HIV protease, HIV-PI likely have additional, yet unidentified, mammalian targets. Individual HIV-PI have been reported to inhibit the proteasome as well as AKT phosphorylation, induce ER stress and exert synergistic cytotoxicity with bortezomib in solid tumors, suggesting a therapeutic potential of HIV-PI especially in myeloma and AML. However, testing and comparing the effects of the different HIV-PI in AML or myloma cells, a prerequisite to identify the most promising HIV-PI to enter clinical testing, have not yet been performed. Methods: We systematically compared and analysed the effects of all currently approved HIV-PI on proteasome inhibition, cytotoxicity, induction or ER-stress, inhibition of p-AKT, and synergism with bortezomib in human myeloma and AML cell lines and primary cells in vitro. Results: HIV-PI can be divided into two subclasses, based on their activity on myeloma and AML cells: Lopinavir, Nelfinavir, Ritonavir and Saquinavir (LNRS-PI) showed biological and molecular activity at concentrations within or near to therapeutic drug levels (10-20 μ M). All remaining HIV-PI were inactive in this concentration range. The LNRS-PI induced ER stress in a very similar fashion (concentration-dependent increase in expression of the chaperones BIP and PDI at 10 μ M). This translated into a uniform pattern of ER stress-induced apoptosis, as deferred from increased expression of CHOP and cleaved PARP, leading to cell death. Likewise, the concentration-dependent inhibition of AKT-phosphorylation was similarly observed for all LNRS-PI, starting at 10 μ M. The LNRS-PI also showed a uniform synergistic cytotoxic activity with bortezomib at therapeutic drug levels, as observed with myeloma cell lines, as well as AML cell lines and primary cells in vitro. By contrast, all remaining HIV-PI did not show a synergistic effect with bortezomib. To assess the effects of the different HIV-PI on proteasome activity, we used activity-based proteasome-specific probes that visualize the activities of the proteasome β2 and β1/β5 active sites in intact, viable cells. Nelfinavir stood out as the only HIV-PI with proteasome-inhibiting activity at therapeutic drug levels. Nelfinavir led to a dose-dependent decrease in active proteasome β1/β5 as well as β2 species in the concentration range of 10–40 μ M. By contrast, low doses of Lopinavir, Ritonavir or Saquinavir induced proteasome β2 and β1/β5 activity, which then decreased to baseline activity levels upon higher drug concentrations (up to 80 μ M). All remaining HIV-PI had no effect on proteasome activity. When cells were pre-treated with bortezomib, which preferentially inhibits the proteasome β1/β5 subunits, and were then exposed to the different HIV-PI, only Nelfinavir led to an additional inhibition of the proteasomal β1/5 and also β2-activity, while all other HIV-PI did not have such an effect. Strikingly, primary myeloma cells from a patient who was refractory to bortezomib-lenalidomide combination therapy, and which were refractory to Bortezomib 10 nM also in vitro, showed robust (> 90%) cytotoxicity when bortezomib was combined with therapeutic drug levels of Nelfinavir (10 μ M). Conclusions: Nelfinavir is a unique drug in the class of HIV-PI, which leads not only to the induction of ER stress and inhibition of AKT-phosphorylation, but also to proteasome inhibition of all active subunits in intact cells at therapeutic drug levels. It re-sensitizes bortezomib-refractory myeloma cells towards bortezomib treatment. Nelfinavir may therefore be an active drug warranting clinical testing in hematologic malignancies, such as myeloma, mantle cell lymphoma or AML. Disclosures: No relevant conflicts of interest to declare.